Caroline C W Klaver

Erasmus MC | Erasmus MC

Background Acute Retinal Pigment Epitheliitis (ARPE, Krill’s disease) is a rare inflammatory retinal disorder commonly affecting young adults. It often presents unilaterally with central vision disruption, and typically resolves with vision restoration within 6 to 12 weeks. The pathogenesis of ARPE remains a subject of ongoing debate. Adaptive Opti...

Importance Primary open-angle glaucoma (POAG) polygenic risk scores (PRSs) continue to be evaluated in primarily European-ancestry populations despite higher prevalence and worse outcomes in African-ancestry populations. Objective To evaluate how established POAG PRSs perform in African-ancestry samples from the Genetics in Glaucoma Patients of Af...

Fundus images allow for non-invasive assessment of the retinal vasculature whose features provide important information on health. Using a fully automated image processing pipeline, we extract 17 different morphological vascular phenotypes, including median vessels diameter, diameter variability, main temporal angles, vascular density, central reti...

Background Perceived age (PA) has been associated with mortality, genetic variants linked to ageing and several age‐related morbidities. However, estimating PA in large datasets is laborious and costly to generate, limiting its practical applicability. Objectives To determine if estimating PA using deep learning‐based algorithms results in the sam...

We introduce VascX models, a comprehensive set of model ensembles for analyzing retinal vasculature from color fundus images (CFIs). Annotated CFIs were aggregated from public datasets for vessel, artery-vein, and disc segmentation; and fovea localization. Additional CFIs from the population-based Rotterdam Study were, with arteries and veins annot...

Purpose The purpose of this study was to develop a deep learning algorithm for detecting and quantifying incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) and complete retinal pigment epithelium and outer retinal atrophy (cRORA) in optical coherence tomography (OCT) that generalizes well to data from different devices and to v...

Aims This study aimed to evaluate the effectiveness of somatostatin analogues (SA) for cystoid maculopathy (CM) in retinitis pigmentosa (RP) patients. Materials and methods In this retrospective case series, clinical and imaging characteristics of 28 RP patients with CM, unresponsive to carbonic anhydrase inhibitors, were collected from medical ch...

Objective To improve the understanding of the natural disease progression of retinitis pigmentosa GTPaseregulator (RPGR)-associated X-linked retinitis pigmentosa (XLRP). Design A multicenter, prospective, observational natural history study over 24 months. Participants Male participants aged ≥7 years with a pathogenic variant in the RPGR gene, a...

Purpose: Gene-based therapies for inherited retinal dystrophies (IRDs) are upcoming. Treatment before substantial vision loss will optimize outcomes. It is crucial to identify common phenotypes and causative genes in children. This study investigated the frequency of these in pediatric IRD with the aim of highlighting relevant groups for future th...

Introduction Demands for myopia management are rising. A web‐based tool that allows home‐performed self‐assessments of visual acuity (VA) and refractive error may enable hybrid care pathways and aid in identifying those with deteriorating visual performance. The tool has been validated in adult populations, but has yet to be evaluated in children....

In this paper, we present a new approach for uncertainty-aware retinal layer segmentation in Optical Coherence Tomography (OCT) scans using probabilistic signed distance functions (SDF). Traditional pixel-wise and regression-based methods primarily encounter difficulties in precise segmentation and lack of geometrical grounding respectively. To add...

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered ge...

Background Among older people undiagnosed and untreated vision impairment and blindness are common. The leading causes are uncorrected refractive errors and cataracts. Vision problems are associated with a lower quality of life, several health problems, and a higher chance of falling accidents and fractures. To eliminate avoidable vision impairment...

Purpose Glaucoma is an eye disease that is the most common cause of irreversible blindness worldwide. It has been suggested that gut microbiota can produce reactive oxygen species and pro-inflammatory cytokines that may travel from the gastric mucosa to distal sites, for example, the optic nerve head or trabecular meshwork. There is evidence for a...

Aims/Purpose: Inflammation is involved in the pathogenesis of cataract, age‐related macular degeneration (AMD) and possibly open‐angle glaucoma (OAG). We assessed whether the inflammatory potential of diet (quantified using the dietary inflammatory index; DII) affects the incidence of these eye diseases. Serum inflammation markers were investigated...

Aims/Purpose: Glaucoma is an eye disease that is the commonest cause of irreversible blindness worldwide. It has been suggested that gut microbiota can produce reactive oxygen species and pro‐inflammatory cytokines that may travel from the gastric mucosa to distal sites, such as the optic nerve head or trabecular meshwork. There is evidence for a g...

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analys...

Purpose The purpose of this study was to determine the association between eye shape and volume measured with magnetic resonance imaging (MRI) and optical biometry and with spherical equivalent (SE) in children. Methods For this study, there were 3637 10-year-old children from a population-based birth-cohort study that underwent optical biometry (...

Recently, a Y727C variant in the dual-specific 3′,5′-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if (1) PDE11A protein is expressed in the retina...

Purpose The purpose of this study was to investigate if education contributes to the risk of myopia because educational activities typically occur indoors or because of other factors, such as prolonged near viewing. Methods This was a two-sample Mendelian randomization study. Participants were from the UK Biobank, Avon Longitudinal Study of Parent...

Recently, a Y727C variant in the dual-specific 3,5-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if 1) PDE11A protein is expressed in the retina or...

Purpose: To investigate the status of patient education among highly myopic individuals focusing on the presence, sources, content, timing of the education and impact on patients. Methods: Self-reported data were collected through an online 13-item questionnaire consisting of open and multiple-choice questions. The questionnaire was sent to 250...

Purpose: To assess the longitudinal vision-related quality of life among patients with CRB1-associated inherited retinal dystrophies. Methods: A longitudinal questionnaire study included 22 patients with pathogenic CRB1 variants. The National Eye Institute Visual Function Questionnaire (39 items, NEI VFQ-39) was applied at baseline, two-year fol...

The ABCA4 gene is the most frequently mutated Mendelian retinopathy-associated gene. Biallelic variants lead to a variety of phenotypes, however, for thousands of cases the underlying variants remain unknown. Here, we aim to shed further light on the missing heritability of ABCA4-associated retinopathy by analyzing a large cohort of macular dystrop...

Purpose: To report the cumulative incidence and risk factors of second eye involvement after diagnosis of myopic macular neovascularization (MNV) in the first eye. Design: Retrospective analysis of longitudinal data from a tertiary hospital in the Netherlands. Participants: Patients with high myopia (spherical equivalent (SE) < - 6 D), Europea...

Insights into the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness, point towards a complex interplay of genetic and lifestyle factors triggering various systemic pathways. This study aimed to characterize metabolomic profiles for AMD and to evaluate their position in the trias with genetics and lifestyle. This s...

Background: Testosterone may be a possible modifiable risk factor for open-angle glaucoma (OAG) and intraocular pressure (IOP), but evidence has been scarce and conflicting. In this study we evaluated the association of testosterone and its genetic predisposition with incident (i) OAG, IOP, retinal nerve fiber layer (RNFL), and ganglion cell-inner...

To study whether it is possible to differentiate intermediate age-related macular degeneration (AMD) from healthy controls using partial optical coherence tomography (OCT) data, that is, restricting the input B-scans to certain pre-defined regions of interest (ROIs). A total of 15744 B-scans from 269 intermediate AMD patients and 115 normal subject...

Purpose: The purpose of this study was to evaluate the epidemiology, etiology, clinical assessment, investigation, management, and visual consequences of high myopia (≤-6 diopters [D]) in infants and young children. Findings: High myopia is rare in pre-school children with a prevalence less than 1%. The etiology of myopia in such children is dif...

Purpose: To investigate the association of commonly used systemic medications with glaucoma and intraocular pressure (IOP) in the European population. Design: Meta-analysis of eleven population-based cohort studies of the European Eye Epidemiology (E3) consortium. Participants: A total of 143240 participants were included in the glaucoma analy...

Purpose: Myopia (nearsightedness) is a condition in which a refractive error (RE) affects vision. Although common variants explain part of the genetic predisposition (18%), most of the estimated 70% heritability is missing. Here, we investigate the contribution of rare genetic variation because this might explain more of the missing heritability i...

Background: High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER...

Purpose: To study the effectiveness of high-dose atropine for reducing eye growth in Mendelian myopia in children and mice. Methods: We studied the effect of high-dose atropine in children with progressive myopia with and without a monogenetic cause. Children were matched for age and axial length (AL) in their first year of treatment. We conside...

Purpose: To battle the spreading of the COVID-19 virus, nationwide lockdowns were implemented during 2020 and 2021. Reports from China revealed that their strict home confinements led to an increase in myopia incidence. The Netherlands implemented a more lenient lockdown, which allowed children to go outside. We evaluated the association between C...

Deep learning classification models for medical image analysis often perform well on data from scanners that were used during training. However, when these models are applied to data from different vendors, their performance tends to drop substantially. Artifacts that only occur within scans from specific scanners are major causes of this poor gene...

Genome-wide association studies (GWAS) have dissected numerous genetic factors underlying refractive errors (RE) such as myopia. Despite significant insights into understanding the genetic architecture of RE, few studies have validated and explored the functional role of candidate genes within these loci. To functionally follow-up on GWAS and chara...

Purpose: The purpose of this study was to describe the genetic relationship between smoking and glaucoma. Methods: We used summary-level genetic data for smoking initiation, smoking intensity (cigarettes per day [CPD]), intraocular pressure (IOP), vertical cup-disc ratio, and open-angle glaucoma (OAG) to estimate global genetic correlations (rg)...

IntroductionExposure to blue light has seriously increased in our environment since the arrival of light emitting diodes (LEDs) and, in recent years, the proliferation of digital devices rich in blue light. This raises some questions about its potential deleterious effects on eye health. The aim of this narrative review is to provide an update on t...

Age-related macular degeneration (AMD) has a strong genetic basis, but environmental factors such as smoking and a healthy diet can decrease the genetic fate by up to 50%. Current guidelines for clinical management include recommendations for a healthy lifestyle and antioxidant supplementation. However, many ophthalmologists do not inform their pat...

A significant number of individuals with a rare disorder such as Usher syndrome (USH) and (non-)syndromic autosomal recessive retinitis pigmentosa (arRP) remain genetically unexplained. Therefore, we assessed subjects suspected of USH2A-associated disease and no or mono-allelic USH2A variants using whole genome sequencing (WGS) followed by an impro...

Purpose: To understand and compare perspectives of patients and professionals on current ophthalmologic care for high myopia, and to identify challenges and future opportunities. Methods: Self-reported data were collected through two online questionnaires. Patient perspective was obtained from highly myopic members of a patient organisation base...

Background Looking older for one’s chronological age is associated with a higher mortality rate. Yet it remains unclear how perceived facial age relates to morbidity and the degree to which facial ageing reflects systemic ageing of the human body. Objectives To investigate the association between ΔPA and age-related morbidities of different organ...

The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. To date, over 500 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap...

Purpose: Previous studies suggest that caffeine is involved in the pathophysiology of open-angle glaucoma (OAG) and the regulation of the intraocular pressure (IOP). However, prospective studies with availability of repeated measures on coffee and tea consumption are limited. The purpose of this study is to identify if and to what extent coffee and...

Despite comprehensive research efforts over the last decades, the pathomechanisms of age-related macular degeneration (AMD) remain far from being understood. Large-scale genome wide association studies (GWAS) were able to provide a defined set of genetic aberrations which contribute to disease risk, with the strongest contributors mapping to distin...

Purpose: To report long-term treatment outcomes of intravitreal bevacizumab (IVB) in myopic macular neovascularization (MNV). Methods: Retrospective analysis of longitudinal, clinical data of high myopic MNV patients treated with IVB. One-hundred-seventeen eyes of 106 patients were followed from first injection up to 12 years. Outcome measures w...

Purpose Genetic variants identified through population-based genome-wide studies are generally of high frequency, exerting their action in the central part of the refractive error spectrum. However, the power to identify associations with variants of lower minor allele frequency is greatly reduced, requiring considerable sample sizes. Here we aim t...

Purpose To assess the association between the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet and the incidence of open-angle glaucoma (iOAG), as well as the association between iOAG and two other well-established diets in the Netherlands, i.e., the Mediterranean diet and Dutch dietary guidelines. Methods In the Rotterdam S...

Early onset drusen maculopathy (EODM) can lead to advanced macular degeneration at a young age, affecting quality of life. However, the genetic causes of EODM are not well studied. We performed whole genome sequencing in 49 EODM patients. Common genetic variants were analysed by calculating genetic risk scores based on 52 age‐related macular genera...

Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are ‘omics’ technologies, which enable hig...

Background Refractive errors are relatively common all around the world. In particular, early onset myopia is associated with a significant burden in later life. Little is known about refractive errors in preschool children. The aim of this study was to assess the prevalence of spectacle wear, visual acuity and refractive errors in young Dutch chil...

Previous studies suggest that nitric oxide is involved in the regulation of the intraocular pressure (IOP) and in the pathophysiology of open-angle glaucoma (OAG). However, prospective studies investigating the association between dietary nitrate intake, a source of nitric oxide, and incident (i)OAG risk are limited. We aimed to determine the assoc...

Importance: Recent studies suggest that the diabetes drug metformin has a protective effect on open-angle glaucoma (OAG) and age-related macular degeneration (AMD). However, studies have not addressed the critical issue of confounding by indication, and associations have not been evaluated in a large prospective cohort. Objective: To determine t...

High myopia (refractive error ≤ −6 diopters (D)) is a heterogeneous condition, and without clear accompanying features it can be difficult to pinpoint a genetic cause. This observational study aimed to evaluate the utility of whole exome sequencing (WES) using an eye disorder gene panel in European patients with high myopia. Patients with high myop...

Refractive errors are common eye disorders characterized by a mismatch between the focal power of the eye and its axial length. An increased axial length is a common cause of the refractive error myopia (nearsightedness). The substantial increase in myopia prevalence over the last decades has raised public health concerns because myopia can lead to...

Purpose ARMS2 is considered the most enigmatic of the genes for age-related macular degeneration (AMD). We investigated the phenotypic course and spectrum of AMD for the risk haplotype at ARMS2/HTRA1 in a large European consortium. Design Pooled analysis of 4 case-control and 6 cohort studies Participants Ten studies from the European Eye Epidemi...

Objective To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene, and to identify potential clinical endpoints and optimal patient selection for future therapeutic trials. Design International multicenter retrospective cohort study. Subjects 82 patients with GUCY2D-associated COR...

Refractive errors are associated with a range of pathological conditions such as myopic maculopathy and glaucoma and are highly heritable. Studies of missense and putative loss-of-function (pLOF) variants identified via whole exome sequencing (WES) offer the prospect of directly implicating potentially causative disease genes. We performed a genome...

This study describes the clinical spectrum and genetic background of high myopia caused by mutations in the ARR3 gene. We performed an observational case series of three multigenerational families with high myopia (SER≤-6D), from the departments of Clinical Genetics and Ophthalmology of a tertiary Dutch hospital. Whole-exome sequencing (WES) with a...

Importance High myopia incidence and prevalence is increasing worldwide, and the visual burden caused by myopia is expected to rise accordingly. Studies investigating the occurrence of myopic complications in individuals of European ancestry with high myopia are scarce, hampering insights into the frequency of myopic retinal complications in Europe...

Inherited retinal diseases (IRDs) are a major cause of visual impairment. These clinically heterogeneous disorders are caused by pathogenic variants in more than 270 genes. As 30–40% of cases remain genetically unexplained following conventional genetic testing, we aimed to obtain a genetic diagnosis in an IRD cohort in which the genetic cause was...

Objective To determine the contribution of common and rare genetic risk variants in families with age-related macular degeneration (AMD). Design Case-control study. Participants A family cohort (355 affected, 342 unaffected family members of 144 families with AMD) and an unrelated case-control cohort (1078 cases, 952 controls), recruited from the...

An increasing number of artificial intelligence (AI) systems are being proposed in ophthalmology, motivated by the variety and amount of clinical and imaging data, as well as their potential benefits at the different stages of patient care. Despite achieving close or even superior performance to that of experts, there is a critical gap between deve...

Background: Early identification of AMD can lead to prompt and more effective treatment, better outcomes, and better final visual acuity; several risk scores have been devised to determine the individual level of risk for developing AMD. Herein, the Delphi method was used to provide recommendations for daily practice regarding preventive measures...